LRP regulation of wildtype and CADASIL mutants of Notch3

Summary

Principal Investigator: Michael M Wang
Abstract: DESCRIPTION (provided by applicant): Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a stroke disorder caused by mutations in Notch3. Hallmark pathological features of CADASIL include: rarefication of the extracellular matrix, granular osmiophilic material (GOM) deposition, and Notch3 protein accumulation. Identification of molecular cascades that lead to these abnormalities will potentially lead to therapies which can prevent progression of this debilitating disease. Normal Notch signaling requires trans-endocytosis of the Notch3 ectodomain, resulting in movement of Notch from one cell to another. This process reduces Notch3 levels. We propose that defects in trans-endocytosis result all of the hallmark pathological features of CADASIL. We have recently identified a family of proteins that interacts with Notch3 and participate in trans-endocytosis of Notch3. Preliminary data demonstrates specific physical interactions between Notch3 and LRP1, a protein known for its endocytic function. Our data indicate that LRP1 plays an important role in trans- endocytosis of Notch3, which potentiates Notch3 function. Based on these findings, we suggest the following hypothesis: mutant Notch3 in CADASIL dysfunctionally binds to LRP1, leading to LRP1 malfunction;decreased LRP1 results in inhibition of endocytosis of critical extracellular proteins, including Notch3. We propose to test this hypothesis in three specific aims. First, we will determine at the molecular level whether mutant Notch3 proteins interact differently with LRP1 (compared to WT Notch3). Second, we will determine in cell cultures whether mutant Notch3 inhibits LRP1 dependent endocytosis. Third, we will test our overall hypothesis by examining mice with tissue-specific inactivation of LRP1 to test whether LRP1 is a true target of mutant Notch3 in vivo. These studies may lead to important directions in the treatment of CADASIL, since our main hypothesis indicates that targeting the interaction between mutant Notch3 and LRP1 may slow the disease process. In addition, recent evidence shows that LRP1 participates in vascular dysfunction after stroke;our studies may thus offer additional insights into the mechanisms of how LRP1 in the brain regulates vascular homeostasis. In lay termninology, this proposal will define the precise mechanism of how Notch proteins can be regulated by LRP1. We will determine if CADASIL Notch3 mutants influence LRP1 function, and whether LRP1 dysfunction results in the vascular pathology seen in CADASIL patients.
Funding Period: 2009-08-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Conserved signal peptide of Notch3 inhibits interaction with proteasome
    Yanmei Zhang
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 0622, USA
    Biochem Biophys Res Commun 355:245-51. 2007
  2. ncbi Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy affecting an African American man: identification of a novel 15-base pair NOTCH3 duplication
    Soo Jung Lee
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Arch Neurol 68:1584-6. 2011
  3. pmc Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
    Hairong Dong
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Brain Res 1456:64-71. 2012
  4. pmc Von Willebrand Factor permeates small vessels in CADASIL and inhibits smooth muscle gene expression
    XiaoJie Zhang
    Departments of Neurology X Z, H M, M M W, Molecular and Integrative, Physiology J S, M M W, and Pathology M B, University of Michigan Medical School, Ann Arbor, MI 48109 Department of Neurology, Veterans Administration Ann Arbor Healthcare, System, Ann Arbor, MI 48105 M M W Institute for Neuropathology, Universitatsspital, CH 8091 Zurich E J R Department of Pathology and Center for Alzheimer s Disease and Related Disorders, Southern Illinois University School of Medicine, Springfield, IL 62794 B E M Departments of Pathology M B S L, Neurology B B W, and Public Health Sciences B B W, University of Virginia, Charlottesville, VA 22908
    Transl Stroke Res 3:138-45. 2012
  5. ncbi ABO blood antigens define human cerebral endothelial diversity
    Michael M Wang
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
    Neuroreport 24:79-83. 2013
  6. pmc Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex
    Ryan A Frieler
    Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    J Am Heart Assoc 1:e002584. 2012
  7. pmc Should the STAIR criteria be modified for preconditioning studies?
    Michael M Wang
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan USA
    Transl Stroke Res 4:3-14. 2013
  8. pmc Advanced intimal hyperplasia without luminal narrowing of leptomeningeal arteries in CADASIL
    Hairong Dong
    Department of Neurology, University of Michigan, 7629 Med Sci II 5622, 1137 Catherine St, Ann Arbor, MI 48109, USA
    Stroke 44:1456-8. 2013
  9. pmc Collagen represses canonical Notch signaling and binds to Notch ectodomain
    XiaoJie Zhang
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Int J Biochem Cell Biol 45:1274-80. 2013
  10. pmc Ischemic stroke selectively inhibits REM sleep of rats
    Samreen Ahmed
    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Exp Neurol 232:168-75. 2011

Detail Information

Publications20

  1. pmc Conserved signal peptide of Notch3 inhibits interaction with proteasome
    Yanmei Zhang
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 0622, USA
    Biochem Biophys Res Commun 355:245-51. 2007
    ..Our findings support a multifunctional role for the conserved N-terminal sequence of Notch3: targeting of the protein to the secretory pathway and reduction of cytoplasmic Notch3 expression which may inhibit cytoplasmic functions...
  2. ncbi Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy affecting an African American man: identification of a novel 15-base pair NOTCH3 duplication
    Soo Jung Lee
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Arch Neurol 68:1584-6. 2011
    ....
  3. pmc Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
    Hairong Dong
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Brain Res 1456:64-71. 2012
    ..These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL...
  4. pmc Von Willebrand Factor permeates small vessels in CADASIL and inhibits smooth muscle gene expression
    XiaoJie Zhang
    Departments of Neurology X Z, H M, M M W, Molecular and Integrative, Physiology J S, M M W, and Pathology M B, University of Michigan Medical School, Ann Arbor, MI 48109 Department of Neurology, Veterans Administration Ann Arbor Healthcare, System, Ann Arbor, MI 48105 M M W Institute for Neuropathology, Universitatsspital, CH 8091 Zurich E J R Department of Pathology and Center for Alzheimer s Disease and Related Disorders, Southern Illinois University School of Medicine, Springfield, IL 62794 B E M Departments of Pathology M B S L, Neurology B B W, and Public Health Sciences B B W, University of Virginia, Charlottesville, VA 22908
    Transl Stroke Res 3:138-45. 2012
    ..We tested whether endothelial von Willebrand factor (vWF) accumulates in CADASIL vessels and whether exposure of smooth muscle cells to vWF alters the expression of smooth muscle gene expression...
  5. ncbi ABO blood antigens define human cerebral endothelial diversity
    Michael M Wang
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
    Neuroreport 24:79-83. 2013
    ..Future studies are warranted to determine whether differences in capillary permeability and cerebral autoregulation vary over short distances within the brain...
  6. pmc Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex
    Ryan A Frieler
    Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    J Am Heart Assoc 1:e002584. 2012
    ..In this study, we explore both model- and sex-specific actions of myeloid MR during ischemic stroke...
  7. pmc Should the STAIR criteria be modified for preconditioning studies?
    Michael M Wang
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan USA
    Transl Stroke Res 4:3-14. 2013
    ....
  8. pmc Advanced intimal hyperplasia without luminal narrowing of leptomeningeal arteries in CADASIL
    Hairong Dong
    Department of Neurology, University of Michigan, 7629 Med Sci II 5622, 1137 Catherine St, Ann Arbor, MI 48109, USA
    Stroke 44:1456-8. 2013
    ..We quantified substructure and diameter of leptomeningeal arteries in CADASIL compared with age-matched controls and the very old; in addition, we characterized intimal thickening in CADASIL using immunohistochemistry...
  9. pmc Collagen represses canonical Notch signaling and binds to Notch ectodomain
    XiaoJie Zhang
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Int J Biochem Cell Biol 45:1274-80. 2013
    ..In addition, type I collagen also inhibited Notch signaling and bound to Notch and Jagged. We conclude that type IV and type I collagen repress canonical Notch signaling to alter expression of Notch target genes...
  10. pmc Ischemic stroke selectively inhibits REM sleep of rats
    Samreen Ahmed
    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Exp Neurol 232:168-75. 2011
    ..Further experiments using this experimental model should be performed to investigate the mechanisms and consequences of REM suppression after stroke...
  11. pmc Notch signaling and Notch signaling modifiers
    Michael M Wang
    Neurology Service, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
    Int J Biochem Cell Biol 43:1550-62. 2011
    ..Here, I review current concepts in Notch signaling, with a focus on work from the last decade elucidating novel extracellular proteins that up- or down-regulate signal potency...
  12. pmc Nuclear contrast angiography: a simple method for morphological characterization of cerebral arteries
    He Meng
    Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109 5622, USA
    Brain Res 1261:75-81. 2009
    ..This method should be useful in studies of stroke and cerebral arteriogenesis, which require the accurate assessment of both arterial diameters and endothelial cell density...
  13. pmc Localization of blood proteins thrombospondin1 and ADAMTS13 to cerebral corpora amylacea
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109 5622, USA
    Neuropathology 29:664-71. 2009
    ..We speculate that CA could result from a conglomeration of interacting proteins from degenerating neurons and from extravasated blood elements released after transient breakdown of the blood-brain barrier...
  14. pmc Lysosome-dependent degradation of Notch3
    Lijun Jia
    Departments of Neurology and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 0622, USA
    Int J Biochem Cell Biol 41:2594-8. 2009
    ..In sum, our experiments demonstrate a critical role for lysosomes in the degradation of Notch3, which distinguishes it from Notch1 and Notch4...
  15. pmc Jagged1 expression regulated by Notch3 and Wnt/β-catenin signaling pathways in ovarian cancer
    Xu Chen
    Department of Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
    Oncotarget 1:210-8. 2010
    ..In addition, Wnt/β-catenin pathway activation also up-regulated Jagged1. Both mechanisms may sustain Notch3 signaling in ovarian cancer cells and contribute to the pathogenesis of ovarian carcinoma...
  16. pmc Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia
    Ryan A Frieler
    Department of Internal Medicine, Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Mich 48109, USA
    Stroke 42:179-85. 2011
    ..In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout mice...
  17. pmc Stromal LRP1 in lung adenocarcinoma predicts clinical outcome
    He Meng
    Departments of Neurology, University of Michigan and Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan 48109, USA
    Clin Cancer Res 17:2426-33. 2011
    ..It is expressed in numerous cancers, but its role in lung cancer has not been characterized. Here, we investigate the relationship between LRP1 and lung cancer...
  18. ncbi Hemoglobin expression in neurons and glia after intracerebral hemorrhage
    Yangdong He
    Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA
    Acta Neurochir Suppl 111:133-7. 2011
    ..These results indicate that ICH increases HbA and HbB expression in neurons and glia cells, and that heme and iron may be important factors in inducing endogenous Hb expression after ICH...
  19. pmc Von Willebrand factor inhibits mature smooth muscle gene expression through impairment of Notch signaling
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 8:e75808. 2013
    ..In sum, these studies demonstrate vWF in the vessel wall as a common feature of cerebral SVD; furthermore, we provide a plausible mechanism by which non-hemostatic vWF may play a novel role in the promotion of vascular disease. ..

Research Grants30

  1. Notch, LRP, and MMP in Stroke and Vascular Dementia
    Michael M Wang; Fiscal Year: 2013
    ..Successful identification of a role for these proteins in vascular diseases suggest that these pathways could potentially be targeted to prevent stroke and vascular dementia in veterans. ..
  2. Genetic Basis of Syndromic and Non-Syndromic Congential Heart Defects
    Bernice E Morrow; Fiscal Year: 2013
    ..These studies wilt greatly expand our understanding of the genetic basis of CTDs, and will promote the development of novel therapeutic and preventive strategies. ..
  3. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  4. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  5. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  6. Role of CCN2 and CCN3 in aging and degeneration of the intervertebral disc
    Cassie M Tran; Fiscal Year: 2013
    ..The information provided by the proposed study will provide insight into the role of CTGF and CCN3 in the aging nucleus pulposus. ..
  7. DSL ligand endocytosis in Notch activation
    GERALDINE A WEINMASTER; Fiscal Year: 2013
    ..Knowledge of Notch signaling mechanisms will also contribute to the manipulation of embryonic and adult stem cells for clinical and commercial applications. ..
  8. TSH RECEPTOR MULTIMERIZATION
    TERRY FRANCIS DAVIES; Fiscal Year: 2013
    ....
  9. Genetic and physiological mechanisms of temperature detection and compensation
    Piali Sengupta; Fiscal Year: 2013
    ..compensate for temperature fluctuations? 4) What defines the limits of the range in which these homeostatic mechanisms operate? 5) What are the common principles of temperature detection and compensation among species? ..
  10. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  11. Presenilins and APP in Protein Trafficking
    Huaxi Xu; Fiscal Year: 2013
    ..Results of these studies will greatly facilitate our understanding of AD pathogenesis and aid in the development of therapeutics. ..
  12. Activation of sirtuins to prevent adverse cardiac remodeling after CABG
    Mahesh P Gupta; Fiscal Year: 2013
    ....
  13. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  14. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  15. ALZHEIMER DISEASE RESEARCH CENTER
    HELENA CHANG CHUI; Fiscal Year: 2013
    ..abstract_text> ..
  16. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..